Summary of Work: An extracellular stimulus evokes a specific response from its target cell - for example, it may command the release or uptake of nutrient, promote neurotransmitter release, or initiate muscle contraction. The information inherent in the stimulus is frequently translated into a format that can then be conveyed by intracellular emissaries: the intracellular levels and hence the activities of these second messengers are regulated according to the strength and duration of the original stimulus. This process - signal transduction - is fundamental to how an organism responds and adapts to changes in the environment. Unfortunately, there are many ways it can be disrupted in disease states and by environmental toxins. The adequate treatment of such disturbances requires us to have an understanding of the precise molecular mechanisms that are involved. We study the physiological actions of the inositol polyphosphate second messengers, particularly InsP5 and InsP6. We have discovered that InsP5 is metabolically poised to respond to an appropriate cell stimulus by being metabolized to a novel second messenger - an InsP4 - that regulates Ca2+-dependent Cl- channels in the plasma membrane. These ion channels participate in salt and fluid secretion, smooth muscle contraction, osmoregulation and volume-dependent metabolic effects. We have discovered how an environmental toxin, okadaic acid, perturbs this process and promotes diarrhea. This has led us to propose that protein phosphatase inhibitors may improve cystic fibrosis therapy. With regards to InsP6, we have shown it is a precursor for other important derivatives: the pyrophosphorylated polyphosphates. We are exploring the significance of these novel metabolites, and the information uncovered to date strongly suggests they perform a valuable function: they are high-energy molecules whose turnover is regulated by specific extracellular agonists. - inositol, salmonella, cystic fibrosis, aluminum, gp120, cell signaling, signal transduction, secretion, calcium